1. Field of the Invention
The present invention relates generally to the fields of pharmacology and more specifically to compounds and treatments for pain management, immune disorders, and drug addiction. More particularly, it provides a variety of compositions and methods based on novel opiate analogs having improved δ opioid receptor selectivity.
2. Description of Related Art
Opioid analgesics are well known for their ability to reduce the perception of pain without a loss of consciousness. Opium, the source of natural opiates, contains a variety of opiates including the familiar morphine and codeine. Morphine possesses a variety of effects, among which are increased tolerance to pain (analgesia), somnolence, euphoria, antitussive activity, respiratory depression, constipation and emesis. However, use of morphine is complicated by the highly addictive nature of this narcotic. The scientific community has focused a significant amount of time and effort to find opioid analogs that exhibit the analgesic activity of morphine and related opioids but possess improved oral bioavailability and a diminished risk associated with addiction and other undesirable side effects.
At least three major types of opioid receptors (δ, μ, κ) are involved in the modulation of a variety of opioid effects. In the field of opioid research, selective agonists for the δ-opioid receptor have shown promising therapeutic potential as analgesics without the adverse side effects associated with morphine and other opioid drugs which are selective for the μ-opioid receptor. The published literature contains numerous references to the design and synthesis of novel opioids, but only a few successful attempts have been reported in the development of non-peptide δ-opioid receptor agonists. Several examples of non-peptide ligands have been discovered either by modification of morphine-type alkaloids or by random screening approaches (Portoghese et al., 1993; Knapp et al., 1995; Knapp et al., 1996), but most of these suffer from various problems such as poor selectivity and low efficacy in vivo. Liao et al. (1998) recently reported the design, synthesis, and biological activity of non-peptide compounds that target the δ-opioid receptor. Portoghese et al. (1998) also described modifications of their “message” and “address” concept for designing receptor-specific opioid agonists and antagonists that confer selectivity for the δ-opioid receptor. Other reports of opioids selective for the δ receptor have also appeared (Ananthan et al., 1998; Ananthan et al., 1999; Schiller et al., 1999; Plobeck et al., 2000; Wei et al., 2000; WO 99/67203; WO 99/67206; U.S. Pat. No. 5,298,622; U.S. Pat. No. 4,816,586; U.S. Pat. No. 5,457,208; and U.S. Pat. No. 6,359,111).
However, there remains a need for non-peptide opioid compounds selective for the δ receptor with improved oral bioavailability and a diminished risk associated with addiction and other undesirable side effects.